Vascular endothelium forms a dynamic interface between blood elements and peripheral tissues. Endothelial cells can undergo changes in function that are critical to normal physiological processes, and non- adaptive alterations that are important in the pathogenesis of vascular disease, including the expression of adhesion molecules. E-selectin is an endothelial-leukocyte adhesion molecule that plays a role in recruitment of neutrophils to sites of inflammatory responses. Its expression is dramatically increased by inflammatory cytokines. We have been examining cytokine-induced expression of the E-selectin gene as a model for how gene expression is activated in the endothelial cell. Analysis of the E-selectin promoter reveals a small cytokine response region consisting of three nuclear factor-kappaB (NF-kappaB) elements and a CRE/ATF-like site. The transcription factors that recognize these elements are targets of signaling events leading to induced gene expression. The working hypothesis is that the E-selectin cytokine- induced transcriptional enhancer consists of an enhanceosome, or a specific spatial arrangement of transcription factors and architectural proteins. We propose to study how this structure directs the recruitment of co-activators and chromatin remodeling factors that result in the induction of gene expression. Following induction, the expression of the gene is diminished by an active process that may involve the recruitment of co-repressors. By characterizing the activation and repression of the E-selectin gene it may be possible to elucidate the transcriptional control processes that activate other inducible genes and convert the quiescent endothelium into a dysfunctional vascular element. Such information may provide novel strategies for therapeutic approaches to the important problem of vascular disease.